PROJECT SUMMARY/ABSTRACT This proposal will facilitate the research and career development training of the candidate in his goal to become an established independent investigator with expertise in oral cancer immunology and chemoprevention. In the United States alone, it is expected that there will be 48,330 new cases and 9,570 deaths in 2016. Significantly, there is a disproportionately high mortality rate of oral cancer among African- American males. Therefore, new and effective oral cancer prevention and treatment strategies are desperately needed. Recent clinical and preclinical studies demonstrate the remarkable ability of black raspberries (BRBs) to inhibit tumor formation in the oral cavity. Yet, there is still limited knowledge on which bioactive compounds in BRBs are most important in inhibiting oral cancer, and how they affect the different cells and molecules that make up the oral tumor microenvironment. This knowledge is essential in order to advance the development of BRB phytochemicals in oral cancer prevention and treatment. The goal of this K01 application is to determine the mechanisms underlying oral cancer inhibition by bioactive BRB phytochemicals, with a focus on two essential components of the oral tumor microenvironment known to promote carcinogenesis: (i) myeloid derived suppressor cells (MDSC) and (ii) the pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF). We hypothesize that phytochemicals in BRBs inhibit oral carcinogenesis by preventing MDSC recruitment/activity as well as suppressing MIF signaling pathways, properties which can be exploited in oral cancer intervention. Studies proposed in Specific Aim 1 will determine the impact of BRB phytochemicals on MDSC function during oral cancer. Studies proposed in Specific Aim 2 will determine the effects of BRB phytochemicals on MIF-associated signaling during oral cancer. Finally, proposed studies in Specific Aim 3 will determine the efficacy of combinatorial approaches with BRB phytochemicals for oral cancer prevention and treatment. These studies will expand our understanding of oral cancer inhibition by BRB phytochemicals and advance the application of BRB phytochemicals as complementary therapeutic strategies against oral cancer. To accomplish these research goals and facilitate his transition to research independence, the candidate will enrich his training and expertise in: (i) metabolomics; (ii) biostatistics; and (iii) cancer clinical trials. This will be accomplished through interaction with an experienced and committed team of mentors, formal didactic and hands-on training, and research education and training programs. The proposed training and research activities will assist in the candidate?s transition to an established and productive independent investigator with a research program focused on exploiting the immunomodulatory properties of bioactive phytochemicals to improve cancer prevention and treatment outcomes.